Science and technology

Drug discovery

New light on proteins

AT ANY given time, there are about 7,000 different types of protein molecule in the average human body cell. Almost a third of these are embedded in the cell's outer membrane. Some control the movement of substances into and out of the cell. Some transmit signals from the exterior to the interior. The importance of these roles, and the exposed and accessible nature of membrane proteins, mean that such proteins are frequently the targets of drugs. Indeed, around half of the drugs currently on the market work by interacting with proteins in the cell membrane.

Membrane proteins are, nevertheless, difficult to study. Removing them from their normal environment deprives them of the company of other substances essential for their function. And seeing what is going on often involves chopping them up or modifying them in some way, such as by attaching fluorescent labels, in order to analyse their activity. Such modifications inevitably affect their function. Now, however, Darryl Bornhop at Vanderbilt University, Nashville, and his colleagues at the Scripps Research Institute in La Jolla, California, have come up with a simple, low-cost way of studying membrane proteins unmodified and in situ using a laser. They have just described their technique in Nature Biotechnology.

Their process is called back-scattering interferometry (BSI). The sample is deposited into a microscopic liquid-filled chamber made of glass and is then illuminated by a laser. Light reflected from it forms an interference pattern that can be captured by a camera. The details of this pattern are exquisitely sensitive to what the molecules in the membrane are doing.

In particular, the pattern changes when the proteins creating it interact with other molecules—such as hormones, if they are signalling protein, or their chemical payloads, if they are transporters. This is because such interactions change the speed that light travels through the proteins in question and that, in turn, changes the interference pattern. Using a series of algorithms written by the team, a computer can correlate these changes in the interference pattern with the binding of particular molecules to particular proteins.

To test their new technique, Dr Bornhop and his colleagues made synthetic membranes containing a small protein called GM1. This is a signalling molecule that is also, unfortunately for victims, the target of cholera toxin. When the team mixed their new membranes with cholera toxin, the interference pattern behaved precisely as predicted. They then carried out similar tests using natural membranes and proteins. These included proteins associated with breast cancer, inflammation and pain. They looked, too, at the receptor for GABA, a brain chemical known to be involved (among other things) in relaxation and the regulation of anxiety. Again, BSI provided measurements that agreed with those obtained in other, more laborious ways.

The simplicity of BSI means it should find application in both research and treatment. On the research side, it will help the study of potential drugs before they are deployed in costly clinical trials, and could also be used to look for side effects, which are sometimes caused by drugs binding to proteins in unexpected ways. On the treatment side, it could be used diagnostically to study the binding of antibodies and thus determine if someone has a particular infection, and to help explain why different patients suffering from the same disease sometimes respond differently to the same treatment. That may be because the drugs involved are not binding to the same degree to the membrane proteins of different individuals. BSI would then be able to show the optimum dose for each individual.

To exploit his invention, Dr Bornop has co-founded a company called Molecular Sensing, which is based near San Francisco. He hopes to provide the first BSI machines to research laboratories later this year. Once again, then, the laser—which celebrated its 50th birthday last year and is already used in areas such as surgery—is finding a new use in the advance of medicine.

Hi,
Drug discovery.
One development that will occur against the pharmaceutical companies
drug monopoly is open source drug development". Pressures coming from
the third world availability of life saving drugs will be the impudicus
for such. Patent protection may come under attack.
Regards Dr. Terence Hale